(Sorry this has taken so long for me to respond)
Operationally, the biggest headache has been the fact that MailBundles (extensions offering access into Mail's innards) have to be located by hand. Having a home directory that does not coincide with the boot drive seems not to be a part of the way that the MailBundle installation/APIs think. Similarly, some driver installs end up making strong assumptions that are confused when home and boot drives are not the same.
But, it also seems to be the case that an upgrade to Ventura is the strongest signal yet that Apple is trying to get us to buy big SSDs; as far as I can tell, while my setup was "carried over" to Ventura, the "Users and Groups" dialogs no longer offer the possibility of making the home drive anywhere but the boot drive; if there's a way to do it, it's going to be one of those things that you only get to by knowing the magic shift/control/command key combinations to reveal the advanced dialog.
So, I've been working on making plans for my next machine, rather than hoping I can remedy the situation here. Ventura seems to make this something that you just can't do anymore.